October 16, 2012 Chapter 6 Restriction- Reacts only to, restricted to same MHC-peptide complex that it was selected

d to be activated against There were lots of random nave T cells and we selected the one that would work- NOT that it learnt Alloreactovity Why do we reject transplants so efficiently?...when they dont have the same MHC alleles we do. MHC stands for Major Histocompatibility complex. Why do cytotoxic cells kill cells that dont have self-MHC? Two possibilities What is the T cell seeing in an alloreaction? Seeing all weird peptides Seeing all the weird MHC Either peptide or MHC driven Alloreactivity probably works in a quantitative way. You have hundreds and thousands of MHC molecules on your cells, but peptides are only appearing a few times. To get a good recognition of one of these Suppose you have a T cell with

Foreign peptide with self MHC sort of looks like self-peptide with foreign MHC. Poor match but if it happens thousands and thousands of times it can make up for a good qualitative one.

CDR 2 and CDR 1 (selected to interact with conserved residues in MHC) on the TCR are not hypermutated, they are coded for in germline. Only CDR 3 is funny. Different alleles vBetas and Valphas OF TCR recognize different alleles of MHC. Since your V regions of your TCR have to interact with MHC, you use the V regions that interact with MHC. The ones that dont will still be made and be nave but wont get expanded etc.

Superantigens They sort of do what antigens do, but dont work the way antigens work. Superantigens can have affinity for constant parts fo MHC2 and Beta regions of some v regions TCR, then it glues them together,even if there is no match-no interaction with peptide. TCR thinks it has gotten a good match-it promiscuously activates T cells that have the particular V beta that the bacterial superantigen will see. If you are non-specifically activating T cells -You cant mount a specific response -They will start pouring out lots of inflammatory lead to widespread inflammation which will lead to schock-drastic sudden lowering of blood pressure-inflammation causes leaky blood vessels-blood pressure too low to perfuse organs-massive organ failure. You can also get too much blood clotting in small vessels, making it even more difficult to perfuse organs. Staphyloccoci food poising happens very soon after you eat the food, because it is not an infection. The toxin is made in the food and so you are eating pre-formed toxinunlike salmonella which requires a few more toxins. Can happen if for example peoples wounds get in their food. When you recover to these toxins, you are still susceptible to them because you cant mount a specific response to anything. You want a lot of MHC alleles around so that a virus cant invade by just mutating its peptie a little bit. In areas where Malaria is endemic, a lot of people have a particular MHC allele, invaders without the allele dont do too well. Can work in both directions-equilibrium-host and virus drive each others evolution. Some one introduced European rabbits to------. There were too much rabbits.they decicded to do biological warfare by spreading virus. Immediaetly there was a decline, the population declined almost to o, then it recovered and you got a population of virus resistant bunnies. When they looked at virus, they noticed that throughout the epidemic, it became less virulentthis gives the virus a more effective way of propogating itselfselecting for milder virus and more resistant bunnies.equilibrium Why dont we have like a zillion MHC alleles? If we have too many alleles of MHC, there would be too many selfreactive T cells to be removed. You also need some diseases to keep population fit. Maybe these are receptors for viruses Hole in repertoire

Linkage disequilibrium could create a false result between an allele and a resultbe careful when ascribing certain properties to certain genessome genes are found together more often than not. There are some diseases that are only spread by macrophage

The tremendous numbers of MHCis good for population. Someone will always be able to respond. Classical MHC 1 PRESENT TO cd8 Mhc2 to cd4 cells Anything else is not classical.non-classicalthese either look like MHC molecules and are coded for in MHC region or look like MHC molecules and are coded for outside. Classical MHC molecules-class 1a e.g. HLA-C Non-classical MHC molecules-class 1b Non-classical MHC molecules e.g. HLA-Eall cells use it, it is associated eith beta 2 microglobulin, but there is not a lot of polymorphism. It PRESENTS A PEPTIDE, but the peptide it presents is the leader sequence for other MHC molecules to NK cells. This is an overall reflection of the number of MHC molecules you are making. It will chop them up and load it to NK cells and they will say ahh this cell is making a lot of this . HLA-G (not very polymorphic)Helps in maternal/fetus interface. Why doesnt the mother attack their own fetus. The trophoblast doesnt express MHC 1. If you dont express MHC 1, Cytotoxic cells wont attack it, however NK cells dont like cells without MHC1. HLA-G inhibits natural killer cells MICA & B are danger signalsif cells are virus infected, cancer start aking these,they interact with NKG2D which is an activating receptor for natural killer cells CD1 molecules present lipids to alpha beta T cells have no CD8 OR cd4. FcRn..maternal/fetus interface Because of this receptor that you can transport IG from mother into fetus mainly Ig1 and 3. Receptor also found in endothelial cells lining your blood vesselsblood vessels constantly sip from yours eru-they internalize immunolgloblin and destroy them.however they have receptors in endosomes which return Igg1 and 3 into serum.

In fact a lot of drugs are made with their fc attached to whatever you want. E.g. embrell. It takes tfalpha receptor and links it to Fc ig 1 or 3 region. Trap for TNFvery important inflammatory cytokinealso macrophages recognize fc region and so It can destroy TNFlinking to fc gammas increases life in serum CD1 seems to bind in a different way than classical MHC